Structural basis for substrate specificities of cellular deoxyribonucleoside kinases

Deoxyribonucleoside kinases phosphorylate deoxyribonucleosides and activate a number of medically important nucleoside analogs. Here we report the str ucture of the Drosophila deoxyribonucleoside kinase with deoxycytidine boun d at the nucleoside binding site and that of the human deoxyguanosine kinas e with ATP at the nucleoside substrate binding site. Compared to the human kinase, the Drosophila kinase has a wider substrate cleft, which may be res ponsible for the broad substrate specificity of this enzyme. The human deox yguanosine kinase is highly specific for purine substrates; this is apparen tly due to the presence of Arg 118, which provides favorable hydrogen bondi ng interactions with the substrate. The two new structures provide an expla nation for the substrate specificity of cellular deoxyribonucleoside kinase s.